Compartmentalized and Differential Regulation of NK- and γδ T-Cell Degranulation by Trophoblast-Derived Signals...

Cytotoxic lymphocytes contribute to immune regulation at the maternal-fetal interface, yet their regulating mechanisms during early pregnancy remain elusive. We investigated compartment-specific NK- and γδT-cell degranulation towards trophoblast-derived signals. Blood and decidual mononuclear cells were obtained from non-pregnant women and women in early pregnancy. Spontaneous and trophoblast-mediated degranulation of NK- and γδT-cell subsets was assessed following co-culture with Sw71 extravillous trophoblast-like cells with normal and reduced expression of HLA-G/HLA-C molecules. CD107a-positive frequency and mean fluorescence intensity were quantified by flow cytometry. Statistical analyses included paired testing, multivariate analyses, and false discovery rate correction. Decidual cytotoxic lymphocytes displayed a distinct degranulation profile compared with blood counterparts. At baseline, γδT cells exhibited higher spontaneous degranulation than NK cells. Trophoblast co-culture exerted limited effects on NK-cell degranulation; however, decidual CD56⁺ γδ T cells showed increased degranulation towards trophoblasts with impaired HLA expression. In conclusion, early pregnancy is characterized by a highly compartmentalized regulation of cytotoxic lymphocyte activity. Decidual NK and γδT cells exhibit enhanced degranulation, but only CD56⁺ γδT cells retain substantial responsiveness to trophoblast-derived signals. These findings identify γδT cells as a dynamically regulated cytotoxic population at the maternal-fetal interface, sensitive to local shifts in trophoblast immune signaling.